Project Summary: Precision oncology is still in its infancy, and while groups envision personalizing care based on the responses of individual tumors there are a wide array of potential uses for the data generated by precision medicine pipelines. Examining data from iterative drug screening performed in collaboration with the Englander Institute of Precision Medicine this project seeks to examine the molecular mechanisms that underpin the efficacy of two PI3K inhibitor based combinations. Specifically aim one explore the impact of the PLK phosphorylation of both wildtype and mutant PI3K to understand the ramifications of this interaction and to identify patient populations who could benefit from combination treatment with PLK and PI3K inhibitors. The second aim seeks to understand the impact of the insulin release that occurs with PI3K inhibitor treatments, and to ask if therapeutic responses can be improved by preventing this feedback. In this manner this project will seek to explain the molecular mechanisms that underlie observations from our precision medicine pipeline and seek to identify patient populations that would benefit from these therapeutic approaches.